rs587779798

Variant names:

• chr5-112775742-G-A
• rs587779798
• NM_000038.6:c.531+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112775742-G-A
• chr5-112775742-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1_Moderate PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.531+5G>A variant in APC is an intronic variant which consists of a G>A nucleotide substitution at the +5 position of intron 5 of the APC gene. The results from in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 3 probands meeting 2 phenotype points (PS4_Moderate; PMID:21813337, GeneDX internal cases). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID:25980754, 26681312, Ambry internal case). This variant has similar in silico predictions compared to another splicing variant at that same nucleotide position (c.531+5G>C) (PMID:12010888, 20223039, 19196998, ClinVar ID 279681), which has been classified as likely pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS1_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010191/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 6.98

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.531+5G>A		splice_region_variant, intron_variant	Intron 5 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.531+5G>A		splice_region_variant, intron_variant	Intron 5 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Apr 27, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12010888]. -

May 15, 2025

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000038.6(APC):c.531+5G>A variant in APC is an intronic variant which consists of a G>A nucleotide substitution at the +5 position of intron 5 of the APC gene. The results from in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 3 probands meeting 2 phenotype points (PS4_Moderate; PMID: 21813337, GeneDX internal cases). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 25980754, 26681312, Ambry internal case). This variant has similar in silico predictions compared to another splicing variant at that same nucleotide position (c.531+5G>C) (PMID: 12010888, 20223039, 19196998, ClinVar ID 279681), which has been classified as likely pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS1_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications v2.1.0; date of approval 11/24/2023). -

not provided Pathogenic:1

Oct 26, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as IVS4+5G>A; This variant is associated with the following publications: (PMID: 25980754, 21813337, 26681312) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 29, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.531+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 4 in the APC gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Susswein LR et al. Genet Med. 2016 Aug;18:823-32). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Benign	0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779798; hg19: chr5-112111439;